title: Macrophage LXRα gene therapy ameliorates atherosclerosis as well as hypertriglyceridemia in LDLR(-/-) mice.
abstract: Liver X receptors (LXRs) are implicated in the regulation of cholesterol homeostasis, inflammatory response and atherogenesis. Administration of LXR agonists inhibits the progress of atherosclerosis, and also increases plasma triglyceride levels, representing an obstacle to their use in treating this disease. The objective of this study was to develop an alternative approach that could overcome this obstacle. Eight-week-old low-density lipoprotein receptor-deficient (LDLR(-/-)) mice were transplanted with hematopoietic stem cell (HSC)-enriched bone marrow cells transduced with lentivectors expressing either green fluorescent protein (GFP) (Lenti-SP-GFP, control) or LXRα (Lenti-SP-LXRα) driven by a synthetic macrophage promoter. At 4 weeks post-transplant, the mice were fed with a Western diet for 8 weeks and then killed. Compared with Lenti-SP-GFP mice, the Lenti-SP-LXRα mice had a 30% reduction in atherosclerotic lesions, which was accompanied by increases in levels of macrophage expression of cholesterol efflux genes apolipoprotein E and ATP-binding cassette A1, as well as decreases in plasma inflammatory cytokines interleukin-6 and tumor necrosis factor-α. Intriguingly, a 50% reduction of plasma triglyceride level was also observed. We conclude that HSC-based macrophage LXRα gene therapy ameliorates the development of atherosclerosis along with an unexpected concomitant reduction of plasma triglyceride levels in LDLR(-/-) mice. These findings highlight the potential value of macrophage LXR expression as an avenue for therapeutic intervention against atherosclerosis.
authors.affiliation: Department of Medicine, University of Texas Health Science Center, and South Texas Veterans Health Care System, Audie L Murphy Division, San Antonio, TX 78229-3900, USA.
authors.forename: G
authors.initials: G
authors.lastname: Li
authors.forename: K C
authors.initials: KC
authors.lastname: Biju
authors.forename: X
authors.initials: X
authors.lastname: Xu
authors.forename: Q
authors.initials: Q
authors.lastname: Zhou
authors.forename: C
authors.initials: C
authors.lastname: Chen
authors.forename: A J
authors.initials: AJ
authors.lastname: Valente
authors.forename: W
authors.initials: W
authors.lastname: He
authors.forename: R L
authors.initials: RL
authors.lastname: Reddick
authors.forename: G L
authors.initials: GL
authors.lastname: Freeman
authors.forename: S S
authors.initials: SS
authors.lastname: Ahuja
authors.forename: R A
authors.initials: RA
authors.lastname: Clark
authors.forename: S
authors.initials: S
authors.lastname: Li
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000628:therapy*; D016026:Bone Marrow Transplantation / Q000379:methods; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D015228:Hypertriglyceridemia / Q000628:therapy*; D015850:Interleukin-6 / Q000097:blood; D016086:Lentivirus; D000071518:Liver X Receptors; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D057093:Orphan Nuclear Receptors / Q000235:genetics*; D011973:Receptors, LDL / Q000172:deficiency*; D014161:Transduction, Genetic; D014280:Triglycerides / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
chemical_list: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D001057:Apolipoproteins E; D015850:Interleukin-6; D000071518:Liver X Receptors; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D011973:Receptors, LDL; D014280:Triglycerides; D014409:Tumor Necrosis Factor-alpha